Function of Antidiuretic Hormone (ADH)
Primary Physiological Role
ADH (also known as arginine vasopressin) functions primarily to regulate water balance in the body by increasing water reabsorption in the kidney collecting ducts, thereby concentrating urine and preventing dehydration. 1, 2
Molecular Mechanism of Water Conservation
ADH works through a precise molecular pathway in the kidney:
ADH binds to vasopressin V2 receptors on the basolateral membrane of collecting duct principal cells, triggering a G-protein coupled signaling cascade that activates adenylyl cyclase, increases cyclic AMP production, and stimulates protein kinase A 2
This signaling causes aquaporin-2 (AQP2) water channels to be inserted into the apical membrane of collecting duct cells through exocytosis, allowing water to enter the cells from the tubular lumen 2, 3
Water then exits through constitutively expressed AQP3 and AQP4 channels in the basolateral membrane, moving from the hypotonic tubular fluid into the hypertonic medullary interstitium, thereby concentrating the urine 2, 3
Without ADH influence, as seen in diabetes insipidus, a person would need to drink 5-15 liters of water daily to match urinary losses 4
Regulation of ADH Secretion
The release of ADH is tightly controlled by specific physiological triggers:
Increased plasma osmolality is the primary stimulus for ADH secretion, detected by hypothalamic osmoreceptors 5
Decreased effective circulating volume or blood pressure also triggers ADH release through baroreceptor pathways 5
Hypertonic saline administration increases plasma osmolality and triggers ADH release, while water ingestion decreases plasma osmolality and inhibits ADH secretion 5
Secondary Effects on Sodium Transport
Beyond water reabsorption, ADH has antinatriuretic properties:
ADH increases free water reabsorption through AQP2 channels without directly affecting sodium transport, distinguishing it from aldosterone which directly increases sodium reabsorption 2
ADH regulates sodium transport throughout the distal nephron, from the thick ascending limb through the collecting duct, which partially facilitates osmotic movement of water 6
Clinical Consequences of ADH Dysfunction
Understanding ADH function is critical because dysfunction causes serious disorders:
In congenital nephrogenic diabetes insipidus, mutations in V2 receptors or AQP2 genes prevent ADH from exerting its antidiuretic effect, resulting in inability to concentrate urine despite high ADH levels, with patients presenting with polyuria, inappropriately dilute urine (osmolality <200 mOsm/kg), and hypernatremia 1, 2
In syndrome of inappropriate ADH secretion (SIADH), excessive ADH production causes water retention, leading to hyponatremia (serum sodium <134 mEq/L), hypoosmolality (plasma osmolality <275 mOsm/kg), and inappropriately concentrated urine (>500 mOsm/kg) 7
With excessive ADH secretion, urine output in adults can decrease to as little as 500 mL per day, dangerously diluting blood volume and expanding intracellular volume 4
Therapeutic Applications
ADH analogs have important clinical uses:
Desmopressin acetate (synthetic ADH analog) increases plasma levels of factor VIII activity in patients with hemophilia and von Willebrand's disease Type I, with maximal plasma levels of 300-400% above baseline obtained after infusion of 0.4 mcg/kg 8
Desmopressin serves as replacement hormone therapy for central diabetes insipidus, reducing urinary output, increasing urine osmolality, and decreasing plasma osmolality 8
The structural modification from arginine vasopressin to desmopressin resulted in increased duration of action and decreased vasopressor effects, allowing clinically effective antidiuretic doses below threshold levels for vascular smooth muscle effects 8
Critical Clinical Pitfall
A common and dangerous pitfall is failing to distinguish between SIADH (euvolemic hyponatremia requiring fluid restriction) and cerebral salt wasting (hypovolemic hyponatremia requiring volume replacement), as they present similarly but require opposite treatments 7. Assessment of extracellular fluid status through physical examination and central venous pressure measurement (SIADH: CVP 6-10 cm H₂O vs cerebral salt wasting: CVP <6 cm H₂O) is essential for proper management 7.